Pyrrolidine carboxylate and pyrrolidine amide hair revitalizing agents

ABSTRACT

This invention relates to methods of treating hair loss, through hair revitalization and germination, by administering non-immunosuppresive pyrrolidine carboxylate and pyrrolidine amide compounds.

This application is a divisional of U.S. patent application Ser. No.08/869,426, filed Jun. 4, 1997, now U.S. Pat. No. 5,945,441 entitled“NOVEL PYRROLIDINE CARBOXYLATE HAIR REVITALIZING AGENTS”.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to methods of treating hair loss and stimulatingthe revitalization and germination of hair. More particularly, itrelates to methods of administering pyrrolidine carboxylate compounds asnovel agents for treatment of hair loss and for the germination andrevitalization of hair.

2. Description of the Related Art

Hair loss occurs in a variety of situations. These situations includemale pattern alopecia, alopecia senilis, alopecia areata, diseasesaccompanied by basic skin lesions or tumors, or systematic disorderssuch as nutritional disorders and internal secretion disorders. Themechanisms causing hair loss are very complicated but in some instancescan be attributed to aging, genetic disposition, the activation of malehormones, the loss of blood supply to hair follicles, and scalpabnormalities.

The immunosuppressant drugs FK506, rapamycin and cyclosporin arewell-known as potent T-cell specific immunosuppressants, and areeffective against graft rejection after organ transplantation. It hasbeen reported that topical, but not oral, application of FK506 (Yamamotoet al, J. Invest. Dermatol, 1994, 102, 160-164; Jiang et al., J. Invest.Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al, J.Dermatol. Sci. 1995, 9, 64-69) stimulated hair growth in adose-dependent manner. One form of hair loss, alopecia areata, is knownto be associated with autoimmune activities, hence, immunomodulatorycompounds were expected to demonstrate efficacy for treating that typeof hair loss. The hair growth stimulating effects of FK506 have been thesubject of an international patent filing covering FK506 and structuresrelated thereto for hair growth stimulation (Honbo et al., EP 0 423 714A2). Honbo et al. discloses the use of relatively large tricycliccompounds, known for their immunosuppressive effects, as hairrevitalizing agents.

The hair growth and revitalization effects of FK506 and related agentsare disclosed in many U.S. patents. (Goulet et al., U.S. Pat. No.5,258,389; Luly et al., U.S. Pat. No. 5,457,111; Goulet et al., U.S.Pat. No. 5,532,248; Goulet et al., U.S. Pat. No. 5,189,042; and Ok etal., U.S. Pat. No. 5,208,241; Rupprecht et al., U.S. Pat. No. 5,284,840;Organ et al., U.S. Pat. No. 5,284,877). These patents claim FK506related compounds. Although they do not claim methods of hairrevitalization, they disclose the known use of FK506 for effecting hairgrowth. Similar to FK506 (and the claimed variations in the Honbo et al.patent) the compounds claimed in these patents are relatively large.Further, the cited patents relate to immunomodulatory compounds for usein autoimmune related diseases, for which FK506's efficacy is wellknown.

Other U.S. Patents disclose the use of cyclosporin and related compoundsfor hair revitalization. (Hauer et al., U.S. Pat. No. 5,342,625; Eberle,U.S. Pat. No. 5,284,826; Hewitt et al., U.S. Pat. No. 4,996,193). Thesepatents also relate to compounds useful for treating autoimmune diseasesand cite the known use of cyclosporin and related immunosuppressivecompounds for hair growth.

However, immunosuppressive compounds by definition suppress the immunesystem and also exhibit other toxic side effects. Accordingly, there isa need for non-immunosuppressant, small molecule compounds which areuseful as hair revitalizing compounds.

Hamilton and Steiner disclose novel pyrrolidine carboxylate compoundswhich bind to the immunophilin FKBP12 and stimulate nerve growth butwhich lack immunosuppressive effects, in U.S. Pat. No. 5,614,547.Unexpectedly, it has been discovered that these non-immunosuppressantcompounds promote hair growth with an efficacy similar to FK506. Yettheir novel small molecule structure and non-immunosuppressiveproperties differentiate them from FK506 and related immunosuppressivecompounds found in the is prior art.

SUMMARY OF THE INVENTION

The present invention relates to methods of treating hair loss byadministering pyrrolidine carboxylate and pyrrolidine amide compounds,and particularly N-glyoxyl prolyl esters, as novel hair revitalizing,germination, and regrowth compounds. Although these compounds are knownas having an affinity for FKBP-type immunophilins, they are unexpectedlypotent as hair growth agents. A key feature of the compounds of thepresent invention is that they do not exert any significantimmunosuppressive activity in addition to their hair growth activity.

A preferred embodiment of this invention is a method of revitalizinghair growth which comprises: administering to an animal an effectiveamount of a non-immunosuppressive pyrrolidine carboxylate andpyrrolidine amide compound.

Another preferred embodiment of this invention is a method of hairgermination which comprises: administering to an animal an effectiveamount of a non-immunosuppressive pyrrolidine carboxylate pyrrolidineamide compound.

Another preferred embodiment of this invention is a method of preventinghair loss which comprises: administering to an animal an effectiveamount of a pyrrolidine carboxylate and pyrrolidine amide compound.

Another preferred embodiment of this invention is the treatment of malepattern alopecia, alopecia senilis, alopecia areata, hair loss from skinlesions or tumors, and hair loss from systematic disorders such asnutritional disorders and internal secretion disorders which comprises:administering to an animal an effective amount of a pyrrolidinecarboxylate and pyrrolidine amide compound.

Another preferred embodiment of this invention is the treatment of hairloss resulting from chemotherapy which comprises: administering to ananimal an effective amount of a pyrrolidine carboxylate and pyrrolidineamide compound.

Another preferred embodiment of this invention is the treatment of hairloss resulting from radiation which comprises: administering to ananimal an effective amount of a pyrrolidine carboxylate and pyrrolidineamide compound.

Another preferred embodiment of this invention is the treatment of hairloss which comprises: administering to an animal an effective amount ofa pyrrolidine carboxylate and pyrrolidine amide compound.

Yet another embodiment of this invention is treating hair loss andstimulating revitalization and germination which comprises:administering to an animal an effective amount of a N-(glyoxyl)prolylester.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of C57 Black 6 mice before being shaved for theexperiment. FIG. 1 shows the condition of the mice prior to theexperiment.

FIG. 2 is a photograph of mice treated with vehicle (Example 2) aftersix weeks. FIG. 2 shows that less than 3% of the shaved area is coveredwith new hair growth when the vehicle (control) is administered.

FIG. 3 is a photograph of mice treated with of 10 μM of GPI 1046(Example 2) after six weeks. FIG. 3 shows the remarkable effects of thecompounds of the present invention wherein 90% of the shaved area iscovered with new hair growth.

FIG. 4 is a photograph of mice treated with 30 μM of GPI 1046(Example 1) after six weeks. FIG. 4 shows the remarkable ability of thecompounds of the present invention to achieve, essentially, completehair regrowth in the shaved area.

DETAILED DESCRIPTION OF THE INVENTION

The methods of this invention relate to treating hair loss andstimulating hair revitalization and germination, through theadministration of novel non-immunosuppressive hair growth agents.Preferred agents are generically described as pyrrolidine carboxylateand pyrrolidine amide compounds.

Preferred agents used in the present invention are compounds of FormulaI:

wherein

R is selected from the group consisting of a C₁-C₉ straight or branchedchain alkyl or alkenyl group optionally substituted with C₃-C₈cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, Ar₁, where saidalkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionallysubstituted with C₁-C₄ alkyl, C₁-C₄ alkenyl, or hydroxy, where Ar₁ isselected from the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl,3-pyridyl,4-pyridyl, and phenyl, having one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight orbranched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy,benzyloxy, and amino:

X is selected from the group consisting of oxygen, sulfur, methylene(CH₂), or H₂;

Y is selected from the group consisting of oxygen or NR₂; where R₂ ishydrogen or C₁-C₆ alkyl; and

Z is selected from the group consisting of C₂-C₆ straight or branchedchain alkyl or alkenyl,

wherein the alkyl chain is substituted in one or more positions with Ar₁as defined above, C₃-C₈ cycloalkyl, cycloalkyl connected by a C₁-C₆straight or unbranched alkyl or alkenyl chain, and Ar₂ is selected fromthe group consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, andphenyl, having one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or alkenyl, C₁-C₄alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; Z may also bethe fragment:

wherein

R₃ is selected from the group consisting of straight or branched alkylC₁-C₉ optionally substituted with C₃-C₈ cycloalkyl, or Ar₁ as definedabove, and unsubstituted Ar₁;

X₂ is O or NR₅, where R₅ is selected from the group consisting ofhydrogen, C₁-C₆ straight or branched alkyl and alkenyl;

R₄ is selected from the group consisting of phenyl, benzyl, C₁-C₅straight or branched alkyl or alkenyl, and C₁-C₅ straight or branchedalkyl or alkenyl substituted with phenyl; or pharmaceutically acceptablesalts or hydrates thereof.

Other preferred agents used in the present invention areN-(glyoxyl)prolyl ester compounds of Formula II:

wherein

R is a C₁-C₉ straight or branched chain alkyl or alkenyl groupoptionally substituted with C₃-C₈ cycloalkyl, C₃ or C₅ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁, where said alkyl, alkenyl, cycloalkyl orcycloalkenyl groups may be optionally substituted with C₁-C₄ alkyl,C₁-C₄ alkenyl, or hydroxy, and where Ar₁ is selected from the groupconsisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl,3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyl, or phenyl, having one to three substituents which areindependently selected from the group consisting of hydrogen, halo,hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight or branched alkyl oralkenyl, C₁-C₄ alkoxy or C₁-C₄ alkenyloxy, phenoxy, benzyloxy, andamino;

Z is a C₂-C₆ straight or branched chain alkyl or alkenyl, wherein thealkyl chain is substituted in one or more positions with Ar₁ as definedabove, C₃-C₈ cycloalkyl, cycloalkyl connected by a C₁-C₆ straight orunbranched alkyl or alkenyl chain, or Ar₂ where Ar₂ is selected from thegroup consisting of 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or phenyl, havingone to three substituents which are independently selected from thegroup consisting of hydrogen, halo, hydroxyl, nitro trifluoromethyl,C₁-C₆ straight or branched alkyl or alkenyl, C₁-C₄ alkoxy or C₁-C₄alkenyloxy, phenoxy, benzyloxy, and amino; or pharmaceuticallyacceptable salts or hydrates thereof.

Other preferred compounds of the invention include:

3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3 3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,

3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,

3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,

3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate,

3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,

3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,

3-(3-Pyridyl)-1-propyl (2S)-1-(2-cycl-ohexyl-1,2-dioxoethyl)-2-5pyrrolidinecarboxylate,

3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate,

3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,

3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,

3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, and apharmaceutically acceptable salt, hydrate, or a mixture thereof.

The term “N-(glyoxyl)prolyl ester” refers to compounds of Formula II.

The term “pyrrolidine carboxylate” refers to compounds of Formula I andincludes N-(glyoxyl)prolyl esters within the definition.

The methods of the present invention use compounds which can be used inthe form of salts derived from inorganic or organic acids and bases.Included among such acid salts are the following: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemissulfate heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, propionate, succinate, tartrate, thiocyanate, tosylate andundecanoate. Base salts include ammonium salts, alkali metal salts suchas sodium and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salt with organic bases such asdicyclohexylamine salts, N-methyl-D-glucamine, and salts with aminoacids such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups can be quarternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyland diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

The hair revitalization compounds of this invention can be periodicallyadministered to a patient suffering from a hair loss or improper hairgrowth condition. The compounds can also be administered to mammalsother than humans for treatment of various conditions necessitating theprevention of hair loss, hair revitalization, or hair germination.

The novel hair revitalization agents of the present invention are potentinhibitors of rotamase activity and are non-immunosuppressive. Further,for the purposes of this invention, the use of those compounds iseffective in hair revitalization and germination. This activity isuseful to promote hair growth in treating alopecia, male patternalopecia, alopecia senilis, alopecia areata, diseases accompanied bybasic skin lesions or tumors, or systematic disorders such asnutritional disorders and internal secretion disorders.

To be effective therapeutically as treatments for conditions associatedwith hair loss the agents must readily effect the targeted areas. Forthese purposes the compounds of the present invention may beadministered topically in dosage formulations containing conventionalnon-toxic pharmaceutically acceptable carriers.

For application topically to the skin, the compounds can be formulatedin a suitable ointment containing the compound suspended or dissolvedin, for example, a mixture with one or more of the following: mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the compounds can be formulated in a suitable lotion orcream containing the active compound suspended or dissolved in, forexample, a mixture of one or more of the following: mineral oil,sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

Dosage levels on the order of about 0.1 mg to about 10,000 mg of theactive ingredient compound are useful in the treatment of the aboveconditions, with preferred levels of about 0.1 mg to about 1,000 mg. Theamount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It is understood, however, that a specific dose level for any particularpatient will depend upon a variety of factors including the activity ofthe specific compound employed, the age, body weight, general health,sex, diet, time of administration, rate of excretion, drug combination,and the severity of the particular disease being treated and form ofadministration.

The compounds can be administered with other hair revitalizing agents.The dosage level of other hair growth drugs will depend upon the factorspreviously stated and the effectiveness of the drug combination.

SYNTHESIS OF THE COMPOUNDS

Compounds of the invention may be readily prepared as described inScheme I, below.

EXAMPLES

The following examples are illustrative of preferred embodiments ofmethods of use and preparation of compounds of the invention and are notto be construed as limiting the invention thereto. Unless otherwiseindicated, all percentages are based upon 100% of the finalformulations.

Example 1 Synthesis of 3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate. (“GPI1046”)

Synthesis of methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (1).

A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol)in dry methylene chloride was cooled to 0° C. and treated withtriethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 mL) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1.5 hour.After filtering to remove solids, the organic phase was washed withwater, dried over MgSO₄ and concentrated. The crude residue was purifiedon a silica gel column, eluting with 50% ethyl acetate in hexane, toobtain 3.52 g (88%) of the product as a reddish oil. Mixture ofcis-trans amide rotamers; data for trans rotamer given. ¹H NMR (CDCl₃):δ 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79, 3.84(s, 3H total); 4.86 (dd, 1H, J=8.4, 3.3).

Synthesis of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2).

A solution of methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g;10.90 mmol) in 30 mL of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 14.2 mL of a 1.0 M solution of 1,1-dimethylpropylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 mL) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%)of the oxamate as a colorless oil. ¹H NMR (CDCl₃): δ 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H) 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54(m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J=8.4, 3.4).

Synthesis of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (3).

A mixture of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g;8.23 mmol), 1N LiOH (15 mL), and methanol (50 mL) was stirred at 0° C.for 30 minutes and at room temperature overnight. The mixture wasacidified to pH 1 with 1 N HCl, diluted with water, and extracted into100 mL of methylene chloride. The organic extract was washed with brineand concentrated to deliver 1.73 g (87%) of snow-white solid which didnot require further purification. ¹H NMR (CDCl₃): δ 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.25 (m, 1H); 3.53 (dd,2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).

Synthesis of 3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate (4).

A mixture of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (4.58g; 19 mmol), 3-pyridinepropanol (3.91 g; 28.5 mmol),dicyclohexylcarbodiimide (6.27 g; 30.4 mmol), camphorsulphonic acid(1.47 g; 6.33 mmol) and 4-dimethyl aminopyridine (773 mg; 6.33 mmol) inmethylene chloride (100 mL) was stirred overnight under a nitrogenatmosphere. The reaction mixture was filtered through Celite to removesolids and concentrated in vacuo. The crude material was triturated withseveral portions of ether, and the ether portions were filtered throughCelite to remove solids and concentrated in vacuo. The concentratedfiltrate was purified on a flash column (gradient elution, 25% ethylacetate in hexane to pure ethyl acetate) to obtain 5.47 g (80%) of GPI1046 as a colorless oil (partial hydrate). ¹H NMR (CDCl₃, 300 MHz): δ0.85 (t, 3H); 1.23, 1.26 (s, 3H each); 1.63-1.89 (m, 2H); 1.90-2.30 (m,4H); 2.30-2.50 (m, 1H); 2.72 (t, 2H); 3.53 (m, 2H); 4.19 (m, 2H); 4.53(m, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45 Anal. Calcd. forC₂₀H₂₈NO₄−0.25 H₂O: C, 65.82; H, 7.87; N, 7.68, Found: C, 66.01; H,7.85; N, 7.64.

Example 2 Hair Revitalizing Test Example In Vivo Hair Generation Testwith C57 Black 6 Mice

C57 black 6 mice were used to demonstrate the hair revitalizingproperties of Example 1. Referring now to FIGS. 1 and 2 of the drawings,C57 black 6 mice, approximately 7 weeks old, had an area of about 2inches by 2 inches on their hindquarters shaved to remove all existinghair. Care was taken not to nick or cause abrasion to the underlayingdermal layers. The animals were in anagen growth phase, as indicated bythe pinkish color of the skin. Referring now to FIGS. 2, 3 and 4, fouranimals per group were treated by topical administration with 20%propylene glycol vehicle (FIG. 2), 10 μM Example 1 (“GPI 1046”) (FIG. 3)or 30 μM Example 1 (“GPI 1046”) (FIG. 4) dissolved in the vehicle. Theanimals were treated with vehicle or Example 1 (“GPI 1046”) every 48hours (3 applications total over the course of 5 days) and the hairgrowth was allowed to proceed for 6 weeks. Hair growth was quantitatedby the percent of shaved area covered by new hair growth during thistime period.

FIG. 2 shows that animals treated with vehicle only showed a smallamount of hair growth in patches or tufts, with less than 3% of theshaved area covered with new growth. In contrast, FIG. 3 shows thatanimals treated with 10 μM Example 1 (“GPI 1046”) showed dramatic hairgrowth, covering greater than 90% of the shaved area in all animals.Further, FIG. 4 shows that mice treated with 30 μM Example 1 (“GPI1046”) showed essentially complete hair regrowth and their shaved areaswere indistinguishable from unshaven C57 black 6 mice.

Example 3

A lotion comprising the composition shown below may be prepared.

(%) 95% Ethanol 80.0  GPI 1046 10.0  α-Tocopheral acetate  0.01 Ethyleneoxide (40 mole) adducts of hardened castor oil 0.5 purified water 9.0perfume and dye q.s.

Into 95% ethanol are added GPI 1046, α-tocopherol acetate, ethyleneoxide (40 mole) adducts of hardened castor oil, perfume and a dye, andthe mixture is stirred and dissolved, followed by an addition ofpurified water, to obtain a transparent liquid lotion.

The lotion is coated once or twice per day, in an amount of 5 ml eachtime, at a site having marked baldness or alopecia.

Example 4

A lotion comprising the composition shown below may be prepared.

(%) 95% Ethanol 80.0  GPI 1046  0.005 Hinokitiol  0.01 Ethylene oxide(40 mole) adducts of hardened castor oil 0.5 Purified water 19.0 Perfume and dye q.s.

Into 95% ethanol are added GPI 1046, hinokitiol, ethylene oxide (40mole) adducts of hardened castor oil, perfume, and a dye, and themixture is stirred and dissolved, followed by an addition of purifiedwater, to obtain a transparent liquid lotion.

The lotion is coated by spraying once to 4 times per day.

Example 5

An emulsion may be prepared from A phase and B phase having thefollowing compositions.

(%) (A phase) Whale wax 0.5 Cetanol 2.0 Petrolatum 5.0 Squalane 10.0 Polyoxyethylene (10 mole) monostearate 2.0 Sorbitane monooleate 1.0 GPI1046  0.01 (B phase) Glycerine 10.0  Purified water 69.0  Perfume, dye,and preservative q.s.

The A phase and the B phase are respectively heated and melted andmaintained at 80° C., both phases are mixed to be emulsified, and arecooled under stirring to normal temperature to obtain an emulsion.

The emulsion is coated by spraying once to four times per day.

Example 6

A cream may be prepared from A phase and B phase having the followingcompositions.

(%) (A Phase) Fluid paraffin 5.0 Cetostearyl alcohol 5.5 Petrolatum 5.5Glycerine monostearate 33.0  Polyoxyethylene (20 mole) 2-octyidodecylether 3.0 Propylparaben 0.3 (B Phase) GPI 1046 0.8 Glycerine 7.0Dipropylene glycol 20.0  Polyethylene glycol 4000 5.0 SodiumHexametaphosphate  0.005 Purified water  44.895

The A phase is heated and melted, and maintained at 70° C. the B phaseis added into the A phase followed by stirring, and the obtainedemulsion is cooled to obtain cream.

The cream is coated on the skin once to 4 times per day.

Example 7

A hair liquid comprising the composition shown below may be prepared.

(%) Polyoxyethylene butyl ether 20.0  Ethanol 50.0  GPI 1046  0.001Propylene glycol 5.0 Polyoxyethylene hardened castor oil derivative 0.4(ethylene oxide 80 mole adducts) Perfume q.s. Purified water q.s.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol,polyoxyethylene hardened castor oil, GPI 1046, and perfume which aremixed under string, and to the mixture is added purified water, toobtain a hair liquid.

The liquid is coated on the skin once to 4 times per day.

Example 8

A hair shampoo comprising the composition shown below may be prepared.

(%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betainelauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0Polyethylene glycol 5.0 GPI 1046 5.0 Ethanol 2.0 Perfume 0.3 Purifiedwater 69.7 

Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0g of triethanolamine laurylsulfate, 6.0 g of betainelauryldimethylaminoacetate, then a mixture obtained by adding 5.0 g ofGPI 1046, 5.0 g of polyethylene glycol, and 2.0 g of ethylene glycoldistearate to 2.0 g of ethanol, followed by stirring, and 0.3 g ofperfume, are successfully added, and the mixture is heated then cooledto obtain a hair shampoo.

The hair shampoo is used on the scalp once or twice per day.

Example 9

A patient is suffering from alopecia senilis. The compounds of thepresent invention would be administered to the patient. It would beexpected that hair growth would occur.

Example 10

A patient is suffering from male alopecia. The compounds of the presentinvention would be administered to the patient. It would be expectedthat increased hair growth would occur.

Example 11

A patient is suffering from alopecia areata. The compounds of thepresent invention would be administered to the patient. It would beexpected that increased hair growth would occur.

Example 12

A patient is suffering from hair loss resulting from skin lesions. Thecompounds of the present invention would be administered to the patient.It would be expected that increased hair growth would occur.

Example 13

A patient is suf fering from hair loss resulting from tumors. Thecompounds of the present invention would be administered to the patient.It would be expected that increased hair growth would occur.

Example 14

A patient is suffering from hair loss resulting from a systematicdisorder such as a nutritional disorder or internal secretion disorder.The compounds of the present invention would be administered to thepatient. It would be expected that increased hair growth would occur.

Example 15

A patient is suffering from hair loss resulting from chemotherapy. Thecompounds of the present invention would be administered to the patient.It would be expected that increased hair growth would occur.

Example 16

A patient is suffering from hair loss resulting from radiation. Thecompounds of the present invention would be administered to the patient.It would be expected that increased hair growth would occur.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

What is claimed is:
 1. A method of promoting hair germination whichcomprises: administering to an animal in need thereof an effectiveamount of a non-immunosuppressive pyrrolidine carboxylate or pyrrolidineamide compound having an affinity for FKBP-type immunophilins.
 2. Themethod of claim 1 wherein the compound is of the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R isselected from the group consisting of a C₁-C₉ straight or branched chainalkyl or C₂-C₉ straight or branched chain alkenyl C₃ or C₅ cycloalkyl,C₅-C₇ cycloalkenyl, and Ar₁, wherein said alkyl or alkenyl is optionallysubstituted with C₃-C₈ cycloalkyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, orhydroxy, where said cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, Ar₁ is selected from thegroup consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₁ has one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight orbranched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄ alkoxy orC₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is selected from thegroup consisting of oxygen, sulfur, methylene, and H₂; Y is selectedfrom the group consisting of oxygen and NR₂, where R₂ is hydrogen orC₁-C₆ alkyl; and Z is selected from the group consisting of C₂-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, and Ar₂, wherein the C₂-C₆ straight or branched alkyl issubstituted in one or more positions with Ar₁ as defined above, C₃-C₈cycloalkyl, or cycloalkyl connected by a C₁-C₆ alkyl or C₂-C₆ alkenyl,and Ar₂, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; or Z is afragment having the following formula:

wherein R₃ is a C₁-C₉ straight or branched alkyl or unsubstituted Ar₁,wherein said C₁-C₉ straight or branched alkyl is optionally substitutedwith C₃-C₈ cycloalkyl or Ar₁ as defined above; X₂ is O or NR₅, where R₅is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched alkyl, and C₂-C₆ straight or branched alkenyl; and R₄ isselected from the group consisting of phenyl, benzyl, C₁-C₅ straight orbranched alkyl or C₂-C₅ straight or branched alkenyl, and C₁-C₅ straightor branched alkyl or C₂-C₅ straight or branched alkenyl substituted withphenyl.
 3. The method of claim 1 wherein the compound is of the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R is aC₁-C₉ straight or branched chain alkyl or C₂-C₉ straight or branchedchain alkenyl C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, whereinsaid C₁-C₉ straight or branched chain alkyl or C₂-C₉ straight orbranched chain alkenyl is optionally substituted with C₃-C₈ cycloalkyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, where said cycloalkyl orcycloalkenyl is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl,or hydroxy; Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl,wherein said Ar₁ has one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or C₂-C₆ straight orbranched alkenyl, C₁-C₄ alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; Z is a C₂-C₆ straight or branched chain alkyl or C₂-C₆straight or branched chain alkenyl, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ alkyl or C₂-C₆ alkenyl, or Ar₂, wherein said C₂-C₆straight or branched alkyl chain is substituted in one or more positionswith Ar₁, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino.
 4. The methodof claim 1 wherein the compound is selected from the group consistingof: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate, 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,and 3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, or apharmaceutically acceptable salt, hydrate, or mixture thereof.
 5. Amethod of preventing hair loss which comprises: administering to ananimal in need thereof an effective amount of a non-immunosuppressivepyrrolidine carboxylate or pyrrolidine amide compound having an affinityfor FKBP-type immunophilins.
 6. The method of claim 5 wherein thecompound is of the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R isselected from the group consisting of a C₁-C₉ straight or branched chainalkyl or C₂-C₉ straight or branched chain alkenyl, C₃ or C₅ cycloalkyl,C₅-C₇ cycloalkenyl, and Ar₁, wherein said alkyl or alkenyl is optionallysubstituted with C₃-C₈ cycloalkyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, orhydroxy, where said cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, Ar₁ is selected from thegroup consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₁ has one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight orbranched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄ alkoxy orC₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is selected from thegroup consisting of oxygen, sulfur, methylene, and H₂; Y is selectedfrom the group consisting of oxygen and NR₂, where R₂ is hydrogen orC₁-C₆ alkyl; and Z is selected from the group consisting of C₂-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, and Ar₂, wherein the C₂-C₆ straight or branched alkyl issubstituted in one or more positions with Ar₁ as defined above, C₃-C₈cycloalkyl, or cycloalkyl connected by a C₁-C₆ alkyl or C₂-C₆ alkenyl,and Ar₂, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; or Z is afragment having the following formula:

wherein R₃ is a C₁-C₉ straight or branched alkyl or unsubstituted Ar₁,wherein said C₁-C₉ straight or branched alkyl is optionally substitutedwith C₃-C₈ cycloalkyl or Ar₁ as defined above; X₂ is O or NR₅, where R₅is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched alkyl, and C₂-C₆ straight or branched alkenyl; and R₄ isselected from the group consisting of phenyl, benzyl, C₁-C₅ straight orbranched alkyl or C₂-C₅ straight or branched alkenyl, and C₁-C₅ straightor branched alkyl or C₂-C₅ straight or branched alkenyl substituted withphenyl.
 7. The method of claim 5 wherein the compound is of the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R is aC₁-C₉ straight or branched chain alkyl or C₂-C₉ straight or branchedchain alkenyl C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, whereinsaid C₁-C₉ straight or branched chain alkyl or C₂-C₉ straight orbranched chain alkenyl is optionally substituted with C₃-C₈ cycloalkyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, where said cycloalkyl orcycloalkenyl is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl,or hydroxy; Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl,wherein said Ar₁ has one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or C₂-C₆ straight orbranched alkenyl, C₁-C₄ alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; Z is a C₂-C₆ straight or branched chain alkyl or C₂-C₆straight or branched chain alkenyl, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ alkyl or C₂-C₆ alkenyl, or Ar₂, wherein said C₂-C₆straight or branched alkyl chain is substituted in one or more positionswith Ar₁, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino.
 8. The methodof claim 5 wherein the compound is selected from the group consistingof: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate, 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,and 3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, or apharmaceutically acceptable salt, hydrate, or mixture thereof.
 9. Amethod of treating alopecia which comprises: administering to an animalin need thereof an effective amount of a non-immunosuppressivepyrrolidine carboxylate or pyrrolidine amide compound having an affinityfor FKBP-type immunophilins.
 10. The method of claim 9 wherein thecompound is of the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R isselected from the group consisting of a C₁-C₉ straight or branched chainalkyl or C₂-C₉ straight or branched chain alkenyl, C₃ or C₅ cycloalkyl,C₅-C₇ cycloalkenyl, and Ar₁, wherein said alkyl or alkenyl is optionallysubstituted with C₃-C₈ cycloalkyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, orhydroxy, where said cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, Ar₁ is selected from thegroup consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₁ has one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight orbranched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄ alkoxy orC₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is selected from thegroup consisting of oxygen, sulfur, methylene, and H₂; Y is selectedfrom the group consisting of oxygen and NR₂, where R₂ is hydrogen orC₁-C₆ alkyl; and Z is selected from the group consisting of C₂-C₆straight or branched chain alkyl or C₂-C₆ straight or branched chainalkenyl, and Ar₂, wherein the C₂-C₆ straight or branched alkyl issubstituted in one or more positions with Ar₁ as defined above, C₃-C₈cycloalkyl, or cycloalkyl connected by a C₁-C₆ alkyl or C₂-C₆ alkenyl,and Ar₂, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; or Z is afragment having the following formula:

wherein R₃ is a C₁-C₉ straight or branched alkyl or unsubstituted Ar₁,wherein said C₁-C₉ straight or branched alkyl is optionally substitutedwith C₃-C₈ cycloalkyl or Ar₁ as defined above; X₂ is O or NR₅, where R₅is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched alkyl, and C₁-C₆ straight or branched alkenyl; and R₄ isselected from the group consisting of phenyl, benzyl, C₁-C₅ straight orbranched alkyl or C₂-C₅ straight or branched alkenyl, and C₁-C₅ straightor branched alkyl or C₂-C₅ straight or branched alkenyl substituted withphenyl.
 11. The method of claim 10 wherein the compound is of theformula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R is aC₁-C₉ straight or branched chain alkyl or C₂-C₉ straight or branchedchain alkenyl C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, whereinsaid C₁-C₉ straight or branched chain alkyl or C₂-C₉ straight orbranched chain alkenyl is optionally substituted with C₃-C₈ cycloalkyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, where said cycloalkyl orcycloalkenyl is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl,or hydroxy; Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl,wherein said Ar₁ has one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or C₂-C₆ straight orbranched alkenyl, C₁-C₄ alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; Z is a C₂-C₆ straight or branched chain alkyl or C₂-C₆straight or branched chain alkenyl, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ alkyl or C₂-C₆ alkenyl, or Ar₂, wherein said C₂-C₆straight or branched alkyl chain is substituted in one or more positionswith Ar₁, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-Cl₄ alkenyloxy, phenoxy, benzyloxy, and amino.
 12. Themethod of claim 9 wherein the compound is selected from the groupconsisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl (2S)1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate, 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,and 3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, or apharmaceutically acceptable salt, hydrate, or mixture thereof.
 13. Amethod of treating hair loss which comprises: administering to an animalin need thereof an effective amount of a non-immunosuppressivepyrrolidine carboxylate or pyrrolidine amide compound having an affinityfor FKBP-type immunophilins.
 14. The method of claim 13 wherein thecompound is of the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R isselected from the group consisting of a C₁-C₉ straight or branched chainalkyl or C₂-C₉ straight or branched chain alkenyl, C₃ or C₅ cycloalkyl,C₅-C₇ cycloalkenyl, and Ar₁, wherein said alkyl or alkenyl is optionallysubstituted with C₃-C₈ cycloalkyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, orhydroxy, where said cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, Ar₁ is selected from thegroup consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₁ has one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight orbranched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄ alkoxy orC₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is selected from thegroup consisting of oxygen, sulfur, methylene, and H₂; Y is selectedfrom the group consisting of oxygen and NR₂, where R₂ is hydrogen orC₁-C₆ alkyl; and Z is selected from the group consisting of C₂-C₆straight or branched chain alkyl or C₂-C₆ straight or branched chainalkenyl, and Ar₂, wherein the C₂-C₆ straight or branched alkyl issubstituted in one or more positions with Ar₁ as defined above, C₃-C₈cycloalkyl, or cycloalkyl connected by a C₁-C₆ alkyl or C₂-C₆ alkenyl,and Ar₂, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; or Z is afragment having the following formula:

wherein R₃ is a C₁-C₉ straight or branched alkyl or unsubstituted Ar₁,wherein said C₁-C₉ straight or branched alkyl is optionally substitutedwith C₃-C₈ cycloalkyl or Ar₁ as defined above; X₂ is O or NR₅, where R₅is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched alkyl, and C₂-C₆ straight or branched alkenyl; and R₄ isselected from the group consisting of phenyl, benzyl, C₁-C₅ straight orbranched alkyl or C₂-C₅ straight or branched alkenyl, and C₁-C₅ straightor branched alkyl or C₂-C₅ straight or branched alkenyl substituted withphenyl.
 15. The method of claim 13 wherein the compound is of theformula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R is aC₁-C₉ straight or branched chain alkyl or C₂-C₉ straight or branchedchain alkenyl C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, whereinsaid C₁-C₉ straight or branched chain alkyl or C₂-C₉ straight orbranched chain alkenyl is optionally substituted with C₃-C₈ cycloalkyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, where said cycloalkyl orcycloalkenyl is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl,or hydroxy; Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl,wherein said Ar₁ has one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or C₂-C₆ straight orbranched alkenyl, C₁-C₄ alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; Z is a C₂-C₆ straight or branched chain alkyl or C₂-C₆straight or branched chain alkenyl, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ alkyl or C₂-C₆ alkenyl, or Ar₂, wherein said C₂-C₆straight or branched alkyl chain is substituted in one or more positionswith Ar₁, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂C₄ alkenyloxy, phenoxy, benzyloxy, and amino.
 16. The methodof claim 13 wherein the compound is selected from the group consistingof: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate, 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,and 3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, or apharmaceutically acceptable salt, hydrate, or mixture thereof.
 17. Amethod of treating hair loss associated with cancer therapy, wherein thecancer therapy is selected from the group consisting of radiation andchemotherapy, wherein said method comprises: administering to an animalin need thereof an effective amount of a non-immunosuppressivepyrrolidine carboxylate or pyrrolidine amide compound having an affinityfor FKBP-type immunophilins.
 18. The method of claim 17 wherein thecompound is of the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R isselected from the group consisting of a C₁-C₉ straight or branched chainalkyl or C₂-C₉ straight or branched chain alkenyl, C₃ or C₅ cycloalkyl,C₅-C₇ cycloalkenyl, and Ar₁, wherein said alkyl or alkenyl is optionallysubstituted with C₃-C₈ cycloalkyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, orhydroxy, where said cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, Ar₁ is selected from thegroup consisting of 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₁ has one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight orbranched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄ alkoxy orC₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is selected from thegroup consisting of oxygen, sulfur, methylene, and H₂; Y is selectedfrom the group consisting of oxygen and NR₂, where R₂ is hydrogen orC₁-C₆ alkyl; and Z is selected from the group consisting of C₂-C₆straight or branched chain alkyl or C₂-C₆ straight or branched chainalkenyl, and Ar₂, wherein the C₂-C₆ straight or branched alkyl issubstituted in one or more positions with Ar₁ as defined above, C₃-C₈cycloalkyl, or cycloalkyl connected by a C₁-C₆ alkyl or C₂-C₆ alkenyl,and Ar₂, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; or Z is afragment having the following formula:

wherein R₃ is a C₁-C₉ straight or branched alkyl or unsubstituted Ar₁,wherein said C₁-C₉ straight or branched alkyl is optionally substitutedwith C₃-C₈ cycloalkyl or Ar₁ as defined above; X₂ is O or NR₅, where R₅is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched alkyl, and C₂-C₆ straight or branched alkenyl; and R₄ isselected from the group consisting of phenyl, benzyl, C₁-C₅ straight orbranched alkyl or C₂-C₅ straight or branched alkenyl, and C₁-C₅ straightor branched alkyl or alkenyl substituted with phenyl.
 19. The method ofclaim 17 wherein the compound is of the formula:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R is aC₁-C₉ straight or branched chain alkyl or C₂-C₉ straight or branchedchain alkenyl, C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, whereinsaid C₁-C₉ straight or branched chain alkyl or C₂-C₉ straight orbranched chain alkenyl is optionally substituted with C₃-C₈ cycloalkyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, where said cycloalkyl orcycloalkenyl is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl,or hydroxy; Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl,wherein said Ar₁ has one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or C₂-C₆ straight orbranched alkenyl, C₁-C₄ alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; Z is a C₂-C₆ straight or branched chain alkyl or C₂-C₆straight or branched chain alkenyl, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ alkyl or C₂-C₆ alkenyl, or Ar₂, wherein said C₂-C₆straight or branched alkyl chain is substituted in one or more positionswith Ar₁, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino.
 20. Themethod of claim 17 wherein the compound is selected from the groupconsisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl (2S)1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate, 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,and 3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, or apharmaceutically acceptable salt, hydrate, or mixture thereof.
 21. Apharmaceutical composition comprising: (i) an effective amount of anon-immunosuppressive pyrrolidine carboxylate or pyrrolidine amidecompound having an affinity for FKBP-type immunophilins; (ii) a secondhair revitalizing compound; and (iii) a pharmaceutically acceptablecarrier.
 22. The pharmaceutical composition of claim 21 wherein thecompound is of formula I:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R isselected from the group consisting of a C₁-C₉ straight or branched chainalkyl or C₂-C₉ straight or branched chain alkenyl, C₃ or C₅ cycloalkyl,C₅-C₇ cycloalkenyl, and Ar₁, wherein said alkyl or alkenyl is optionallysubstituted with C₃-C₈ cycloalkyl, C₁-C₄ alkyl, C₂-C₄ alkenyl, orhydroxy, wherein said cycloalkyl or cycloalkenyl is optionallysubstituted with C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, Ar₁ is selectedfrom the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₁ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is selectedfrom the group consisting of oxygen, sulfur, methylene, and H₂; Y isselected from the group consisting of oxygen and NR₂, where R₂ ishydrogen or C₁-C₆ alkyl; and Z is selected from the group consisting ofC₂-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl, and Ar₂, wherein the C₂-C₆ straight or branched alkyl issubstituted in one or more positions with Ar₁ as defined above, C₃-C₈cycloalkyl, or cycloalkyl connected by a C₁-C₆ alkyl or C₂-C₆ alkenyl;Ar₂ is selected from the group consisting of 2-indolyl, 3-indolyl,2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one to threesubstituents which are independently selected from the group consistingof hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆ straight orbranched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄ alkoxy orC₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; or Z is a fragmenthaving the following formula:

wherein R₃ is a C₁-C₉ straight or branched alkyl or unsubstituted Ar₁,wherein said C₁-C₉ straight or branched alkyl is optionally substitutedwith C₃-C₈ cycloalkyl or Ar₁ as defined above; X₂ is O or NR₅, where R₅is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched alkyl, and C₂-C₆ straight or branched alkenyl; and R₄ isselected from the group consisting of phenyl, benzyl, C₁-C₅ straight orbranched alkyl or C₂-C₅ straight or branched alkenyl, and C₁-C₅ straightor branched alkyl or C₂-C₅ straight or branched alkenyl substituted withphenyl.
 23. The pharmaceutical composition of claim 21 wherein thecompound is of formula II:

or a pharmaceutically acceptable salt or hydrate thereof, wherein R is aC₁-C₉ straight or branched chain alkyl or C₂-C₉ straight or branchedchain alkenyl C₃ or C₅ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, whereinsaid C₁-C₉ straight or branched chain alkyl or C₂-C₉ straight orbranched chain alkenyl is optionally substituted with C₃-C₈ cycloalkyl,C₁-C₄ alkyl, C₂-C₄ alkenyl, or hydroxy, wherein said cycloalkyl orcycloalkenyl is optionally substituted with C₁-C₄ alkyl, C₂-C₄ alkenyl,or hydroxy; Ar₁ is selected from the group consisting of 1-naphthyl,2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl,wherein said Ar₁ has one to three substituents which are independentlyselected from the group consisting of hydrogen, halo, hydroxyl, nitro,trifluoromethyl, C₁-C₆ straight or branched alkyl or C₂-C₆ straight orbranched alkenyl, C₁-C₄ alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy,and amino; Z is a C₂-C₆ straight or branched chain alkyl or C₂-C₆straight or branched chain alkenyl, C₃-C₈ cycloalkyl, cycloalkylconnected by a C₁-C₆ alkyl or C₂-C₆ alkenyl, or Ar₂, wherein said C₂-C₆straight or branched alkyl chain is substituted in one or more positionswith Ar₁, Ar₂ is selected from the group consisting of 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, and phenyl, wherein said Ar₂ has one tothree substituents which are independently selected from the groupconsisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched alkyl or C₂-C₆ straight or branched alkenyl, C₁-C₄alkoxy or C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino.
 24. Thepharmaceutical composition of claim 21 wherein the compound is selectedfrom the group consisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-prop-2-(E)-enyl (2S)-1-(3,3,-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-propyl (2S)-1-(3,3,dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])entyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate,3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2,phenyl)ethyl-2-pyrrolidinecarboxylate, 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate,3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate,and 3,3-Diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, or apharmaceutically acceptable salt, hydrate, or mixture thereof.